Viral infections have plagued human allogeneic transplant patients by causing illness and being associated with graft versus host reactions and transplant rejections. Transplant patients are vulnerable to viruses because viruses can be transferred or reactivated by the transplantation procedure and because of the immunosuppressive treatment the patients receive to tolerate the allografts. My colleagues have shown in animal models of allogeneic skin and pancreatic islet transplantation that the need for continued immunosuppressive therapy can be bypassed by pre-exposure of the recipient to a donor allogeneic splenocyte transfusion (DST) in the presence of a two-week regimen of antibody to CD40-ligand (CD154). This tolerizes the host to the allogeneic tissue, and this tolerance lasts well over a year. An important issue is whether viral infections can overcome this tolerance and induce graft rejection and whether the DST anti-CD154 tolerization compromise the host's ability to clear viral infections. We have recently determined that lymphocytic choriomeningitis virus (LCMV) induces the rejection of newly transplanted but not 50-day transplanted skin allografts in mice. We propose to examine in this model why this rejection takes place early but not late after transplantation, whether murine cytomegalovirus and several other viruses can induce such rejection, and whether the tolerization process comprises the host's ability to control these infections. Information gained from this study will help determine the vulnerability of transplant patients to viral infections and aid in developing strategies to shield vulnerable patients from infection as this new technique begins clinical trials.